Journal
JOURNAL OF CONTROLLED RELEASE
Volume 324, Issue -, Pages 471-481Publisher
ELSEVIER
DOI: 10.1016/j.jconrel.2020.05.027
Keywords
Chronic toxicity; Nanotoxicology; Silica nanoparticles; Porosity; Hemocompatibility; Complement; One-year; BALB/c mice
Funding
- National Institute of Environmental Health Sciences of the National Institutes of Health [R01ES024681]
- ALSAM Foundation
- National Cancer Institute of the National Institutes of Health under CCSG [CA042014-31]
- MRSEC Program of the National Science Foundation [DMR-1121252]
- National Cancer Institute, National Institutes of Health [HHSN261200800001E, 75N91019D00024]
Ask authors/readers for more resources
Chronic toxicity evaluations of nanotechnology-based drugs are essential to support initiation of clinical trials. Ideally such evaluations should address the dosing strategy in human applications and provide sufficient information for long-term usage. Herein, we investigated one-year toxicity of non-surface modified silica nano particles (SNPs) with variations in size and porosity (Stober SNPs 46 +/- 4.9 and 432.0 +/- 18.7 nm and mesoporous SNPs 466.0 +/- 86.0 nm) upon single dose intravenous administration to female and male BALB/c mice (10 animal/sex/group) along with their human blood compatibility. Our evidence of clinical observation and blood parameters showed no significant changes in body weight, cell blood count, nor plasma biomarker indices. No significant changes were noted in post necropsy examination of internal organs and organ-to-body weight ratio. However, microscopic examination revealed significant amount of liver inflammation and aggregates of histocytes with neutrophils within the spleen suggesting an ongoing or resolving injury. The fast accumulation of these plain SNPs in the liver and spleen upon IV administration and the duration needed for their clearance caused these injuries. There were also subtle changes which were attributed to prior infarctions or resolved intravascular thrombosis and included calcifications in pulmonary vessels, focal cardiac fibrosis with calcifications, and focal renal injury. Most of the pathologic lesions were observed when large, non-porous SNPs were administered. Statistically significant chronic toxicity was not observed for the small non-porous particles and for the mesoporous particles. This one-year post-exposure evaluation indicate that female and male BALB/c mice need up to one year to recover from acute tissue toxic effects of silica nanoparticles upon single dose intravenous administration at their 10-day maximum tolerated dose. Further, ex vivo testing with human blood and plasma revealed no hemolysis or complement activation following incubation with these silica nanoparticles. These results can inform the potential utility of silica nanoparticles in biomedical applications such as controlled drug delivery where intravenous injection of the particles is intended.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available